HIV protease inhibitors have been successfully used in highly active anti-retroviral therapy (HAART) for HIV infection. Incorporation of protease inhibitors in HAART causes profound and sustained suppression of viral replication, significantly reduces the morbidity and mortality, and prolongs the lifespan of patients with HIV infection. Unfortunately, the benefits of HIV protease inhibitors are compromised by a number of metabolic abnormalities. One of the most deleterious side effects of HIV protease inhibitor therapy is the development of dyslipidemia, which is a well established risk factor for the development of atherosclerosis. However, the exact mechanisms by which HIV protease inhibitors promote atherosclerosis remain unclear. Macrophages are the most prominent cell type involved in atherosclerotic lesions and play key roles in all phases of atherosclerosis. A portion of macrophages become apoptotic, particularly in advanced lesions, which is regulated or controlled by numerous factors. One critical step for inducing macrophage apoptosis is to disrupt endoplasmic reticulum (ER) homeostasis, thus triggering the ER stress signal transduction pathway, known as the unfolded protein response (UPR). UPR plays a critical role in regulating cell growth, differentiation, and apoptosis. Importantly, the UPR has been linked to macrophage apoptosis in atherosclerotic lesions. Our preliminarily data demonstrate that treatment with HIV protease inhibitors increases the accumulation of intracellular free cholesterol, activates the UPR, and induces apoptosis in macrophages. Based on these novel findings, we HYPOTHESIZE that HIV protease inhibitors promote atherosclerosis by disrupting lipid homeostasis, activating the UPR, and inducing apoptosis in macrophages. Three specific aims are proposed to test the hypothesis. Aim#1: To determine the effects of clinically used HIV protease inhibitors on UPR activation both in cultured macrophages and in vivo. Aim#2: To elucidate the cellular/molecular mechanisms leading to UPR activation by HIV protease inhibitors in macrophages. Aim#3: To determine whether HIV protease inhibitor-induced UPR activation is responsible for the formation of atherosclerotic lesions in vivo mouse models. Completion of these specific aims will help identify and establish new cellular/molecular mechanisms of HIV protease inhibitor-induced atherosclerosis, thereby enhancing our understanding of the mechanisms of HAART-associated cardiovascular diseases and providing novel information for the development of new therapeutic strategies. [unreadable] [unreadable] [unreadable]